The present invention deals with the combination of various synergistic antioxidants, enzymatic co-factors and amino acids in appropriate delivery vehicles employed in cigarette filters and in external filters such as cigarette and cigar xe2x80x9cholders,xe2x80x9d in xe2x80x9cpipe filtersxe2x80x9d and in tobacco, wrappers and papers and in so-called smokeless tobacco as a means of preventing or ameliorating signs and symptoms and complications to the oro-pharyngeal cavity, respiratory tract and lungs from damage by tobacco smoke and tobacco chewed induced free radical species. The present invention can be employed in filter cigarettes, unfiltered cigarettes, cigars, pipes, and smokeless tobacco products.
The deleterious effects of tobacco abuse are well known and regulatory agencies as well as the public constantly react to these scientific and epidemiologic evidences. Tobacco is indeed a worldwide public health hazard accounting for significant morbidity and mortality. Although smoking places an abundant oxidant insult to the oral cavity, respiratory tract and lungs, evidence supports the notion that the oxidant burden is on the entire organism of the smoker. Smoking promotes development or enhancement of atherosclerosis, causing cardiovascular disease, chronic obstructive pulmonary disease, recently labeled xe2x80x9csmoker""s lung,xe2x80x9d cutaneous damage, especially to the face, called xe2x80x9csmoker""s face,xe2x80x9d and various forms of cancer, including carcinomas of the mouth, pharynx, esophagus and lung.
Tobacco is a substance consisting of the dried leaves and stems of the plant Nicotiana tabacum. Tobacco contains the drug nicotine, which is very addictive. The plant is native to North America and now is grown worldwide. Tobacco abuse has been identified as the single most preventable cause of disease, morbidity and mortality, for tobacco smoke contains many toxic chemicals, in tar and gas phase smoke.
There are three principal ways to consume tobacco: 1) smoking, 2) chewing and dipping, and 3) snuffing. Fifty million Americans smoke, and countless others are affected by tobacco smoke, the so called secondary or environmental smokers. Children of smokers also breathe this second-hand smoke and have more respiratory problems than children of non-smokers. Smokeless tobacco is used by as many as 12 million individuals and has detrimental effects on the oral cavity plus systemic effects derived from buccal absorption of nicotine and other chemicals.
Cigarette smoke is divided into two phases, tar and gas-phase smoke. Cigarette tar contains high concentrations of free radicals. Common oxidants include semiquinone which is in equilibrium with hydroquinones and quinones, particularly in the viscous tar matrix. Many tar extracts and oxidants, including the latter mentioned, are water soluble and reduce oxygen to its superoxide radical which can dismutate to form H2O2. Importantly, glass-fiber type cigarette filters retain almost all of the tar particles that are larger than 0.1 micron. Thus, the filter acts as a trap for tars in cigarette smoke. There are an inordinately large number of free radicals, greater than 1015, in each puff in the gas-phase of cigarette smoke. While oxidants in tar are stable, those organic radicals in gas phase smoke are reactive carbon and oxygen centered radicals with extremely short half lives. Other free radical species, such as the aldehyde species have longer half-lives and may be more deleterious, resulting from lipid peroxidation. Interestingly, concentrations of free radicals from tobacco are maintained at high levels for more than 10 minutes and tend to increase as tobacco smoke is aged. It is thus considered that these gas phase smoke oxidants are in a steady state as they are both continuously formed and destroyed. The latter reactions are similar to those noted to occur in smog, pointing to the extra noxious stimuli to primary and secondary smokers in atmospheric polluted environments.
Various studies have correlated the importance of oxidant stress to various organs resulting from tobacco smoke and other noxious environmental factors and thus continue to exert a toll on the public health of all countries. Significant morbidity and mortality result from smoking tobacco from cigarettes, cigars, and pipes and local oral pathology from both smoking and chewing tobacco. Epidemiologic studies have strongly implicated tobacco in the pathogenesis of atherosclerosis and coronary artery disease, emphysema and various malignancies, including oro-pharyngeal and pulmonary neoplasias. Chronic cigarette smoking is associated with appearance of free radicals inducing oxidative damage. Measurement in blood, urine and tissues of various antioxidants or of by-products of free radical metabolic processes are supportive of tissue oxidant damage in the pathogenesis of various diseases associated with tobacco smoking and environmental pollutants.
Studies have estimated that tobacco smoke has over 3,000 different constituents, of which a number are toxic, some are carcinogenic and many generate free radical species. Most of these compounds have been identified in so-called mainstream and sidestream tobacco smoke. The former is that volume of smoke drawn through the mouthpiece of the tobacco product during puffing while sidestream smoke is that smoke emitted from the smoldering cigarette in between puffs. Although tar and nicotine are retained in the filter of cigarettes, the present invention applies mainly to mainstream smoke, be it drawn through filtered and non-filtered cigarettes. It is noted that the emissions of toxic and carcinogenic components in sidestream smoke are not significantly reduced in filter cigarettes when compared to their non-filter counterparts. Thus, sidestream smoke is a major contributor to environmental smoke, affecting both the smoker and their non-smoking counterparts, so called secondary smokers. The lower rates of consumption of cigarettes with high smoke yields has not reduced the indoor pollutants of carcinogenic substances and free radicals generating potential of tobacco smoke produced in sidestream smoke, albeit their diminished levels in mainstream smoke by smoking low yield tobaccos and filtered cigarettes.
Leukoplakia, a tobacco induced white patch on the buccal mucosa, as found in smokers, is a localized irritation due to direct contact of smoked tobacco and it is directly related to the frequency and years of tobacco abuse. Although leukoplakia is a benign oral lesion, these have a malignant potential, requiring a biopsy of the lesion to rule out cancer. Leukoplakia may regress or resolve completely when use of tobacco products is discontinued.
Over 30,000 new cases of cancer of the oral cavity are diagnosed annually, accounting for two to four percent of all new cancers. Oral cancer kills 8,000 patients each year and only half of cases diagnosed annually have a five year survival. The great majority of these patients are users of tobacco products. Other risk factors include alcohol abuse, nutritional deficiencies and poor oral hygiene.
Tobacco contributes to other oral symptoms or pathologies of the mouth and teeth. Tobacco may cause halitosis, may numb the taste buds, interfere with the smell and the taste of food and may stain teeth and contribute to dental caries. For example, smokers have more dental tartar (calculus) than non-smokers. Tobacco is also associated with destructive periodontal (gum) disease and tooth loss. Acute necrotizing ulcerative gingivitis (xe2x80x9ctrench mouthxe2x80x9d) is a destructive, painful inflammatory condition occurring mainly in cigarette smokers. Swelling of the nasal and sinus membranes have also been associated, purportedly, in individuals who are xe2x80x9callergicxe2x80x9d to tobacco smoke.
Tobacco, whether smoked as cigarettes, cigars or pipes causes common untoward effects in the oral cavity. Tobacco smoke has two chances to exert its deleterious effects in the mouthxe2x80x94when it is inhaled by the smoker and on its exit during exhalation.
Like cigarettes, evidence shows that cigars are also toxic and addictive. Cigar and cigarette smokers have a similar increased risk for oral and laryngeal cancers but the latter smokers are more prone to contract cancer of the lung, emphysema and cardiovascular disease. While cigarette tobacco is generally flue cured with a resulting mildly acidic product, the slower curing methods for cigars render these mildly alkaline. At this pH, nicotine is more readily absorbed. Unlike cigarettes, cigars are less homogenous and vary in size and nicotine content. Cigar smokers may spend an hour smoking a single large xe2x80x9cHavanaxe2x80x9d although some actively inhale very little of this smoke; however, in non-inhalers, their nicotine levels may be elevated with no toxic co-absorption, as occurs in cigarette smokers. Cigar smokers also commonly hold an unlit cigar in the mouth, exposing the oral cavity to further nicotine by local absorption. Thus, consumption of cigars may produce an equal or greater smoke burden of exposure and locally generated free radicals in the oral cavity which create deleterious effects and a risk of oro-pharyngeal cancer.
Carcinoma of the lung and chronic lung disease have been known to be end stage complications of cigarette abuse. Nicotine tars contain carcinogens and smoking also induces a free radical reaction in the respiratory tract, both putative to the oro-pharyngeal and pulmonary diseases and neoplasias induced by tobacco abuse. Cigarette filters xe2x80x9ctrapxe2x80x9d nicotine tars but not the gas-phase compounds. Epidemiologic studies have been done in various countries to show the differential effects of tar content, amount of cigarettes smoked, type of tobacco smoked, and use of filters on oro-pharyngeal and lung cancer risk in cigarette smokers.
Under the epithelial lining along the respiratory airways there is a rich network of micro vessels which carry systemic blood from the nasal and tracheobronchial arteries. These vessels provide nutrition to the mucosa to enable it to maintain the protective functions. This first line of defense initially is non-injurious and reversible, but overwhelming or chronic and persistent stimuli, as tobacco smoke and other environmental pollutants, may cause pulmonary damage from the oxidative damage of the leucocytes, other free radicals and noxious agents.
In other in vitro studies, gas-phase cigarette smoke was assessed in its filtered and whole (unfiltered) states for oxidative effects on human plasma. Investigators noted the prevalence of lipid peroxidation in plasma after exposure to gas phase smoke, but not to whole cigarette smoke. The reaction of lipid peroxidation did not commence until the endogenous ascorbic acid had been consumed, that is, vitamin C was oxidized completely. They also noted that cigarette smoke exposure caused oxidation of plasma protein thiols (methionine and cysteine amino acid linkages) and low density lipo-proteins. They concluded that lipid peroxidation induced by the oxidants of gas-phase smoke leads to changes in lipoproteins associated with atherogenesis. As noted herein, the synergistic effect of reduced glutathione and ascorbic acid or ascorbic acid derivatives such as their esters, are beneficial in combating tobacco oxidants and in both ameliorating and delaying the effects of tobacco smoke on oral, pharyngeal and respiratory epithelia, on bronchoalveolar fluids and on lung parenchyma.
Cells subjected to oxidative stress may severely affect cellular function and cause damage to membrane lipids, to proteins, to cytoskeletal structures and to DNA. Free radical damage to DNA has been measured as formation of single-strand breaks, double-strand breaks and chromosomal aberrations. Cells exposed to ionizing radiation and cigarette smoke have also been demonstrated to have an increased intracellular DNA damage, hence the frequency of oro-pharyngeal, esophageal, and pulmonary carcinomas in tobacco users.
The lungs have adapted biochemical enzymatic and non-enzymatic antioxidant systems as prevention, limitation or reversal of oxidant damage to the lungs. This is a protective feature to maintain normal pulmonary function, as the respiratory tissues operate in an environment of high partial pressure of oxygen and are continuously exposed to airborne pollutants. Because of their access to the environment, like the skin to oxygen and ultraviolet radiation, the lungs may be damaged by inhaled gaseous and particulate matter, particularly in both active and passive smokers.
Reactive oxidizing species, as induced by inhaled tobacco, smoke, ozone smog and others are important factors in bronchial hyperresponsiveness and inflammatory lung injury. As in other tissues, antioxidant enzymes in the lung include superoxide dismutase (SOD), which converts superoxide to hydrogen peroxide and catalase which reduces hydrogen peroxide to water. This reaction may also be catalyzed by the selenium cofactor enzyme glutathione peroxidase using reduced glutathione (GSH) as a substrate. Glutathione peroxidase may also reduce lipid peroxide to the corresponding alcohols also using reduced glutathione.
The ubiquitous non-enzymatic thiol tripeptide, glutathione (GSH), plays a vital function in maintaining the integrity of the reactive oxygen species-free radical sensitive cellular components. This is accomplished through its direct role as an antioxidant, in its reduced (GSH) form, as well as a cofactor, as aforementioned. GSH has been detected in bronchoalveolar lavage fluid. In cells, GSH is oxidized in this process to GSSG, but its cellular concentrations for antioxidant activity is maintained in equilibrium by the enzyme glutathione reductase, consuming NADPH as the source of reducing equivalents. Under states of GSH depletion, including malnutrition and severe oxidative stress, as in smoking, cells may become injured and die.
The solid phase (tar) of tobacco contains high concentrations of stable free radicals. These have been identified as semiquinones which are in equilibrium with quinones and hydroxyquinones. These free radicals are capable then of reducing molecular oxygen to form the toxic free radical called superoxide. Superoxide, upon dismutation, can form the injurious molecule hydrogen peroxide (H2O2). The typical Cambridge glass-fiber filter is able to withhold over 99% of particles greater than 0.1 um, but this filter does not trap superoxide or H2O2, which are thus inhaled by the smoker. However, gas-phase smoke contains over 1015 organic radicals per each puff. In contrast to stable free radicals, these have a half-life of 1 second yet are capable of maintaining their high levels of activity in the gas phase smoke for over 10 minutes. This smoke also results in the creation of the H2O2 through the smoke""s production of the toxic hydroxyl radical. The present invention recognizes that the enzyme superoxide dismutase reduces the toxicity of the hydroxyl radical by the dismutation reaction to make the relatively less toxic H2O2. However, to reduce H2O2 and other peroxide molecules, the enzymes catalase and glutathione peroxidase are required. The former, catalase, reduces H2O2 to water and O2.
Hydrogen peroxide, like other tobacco generated free radicals, have been implicated in the etiology of oro-pharyngeal malignancy and pulmonary neoplasms, in smokers. H2O2 reacts with the DNA in cells and causes breaks in the double strand which lead to mutations, precursors of malignant cells.
Cigarette smoke also contains aldehydes which are capable of altering protein function by increasing the rate of catabolism. Aldehydes also cause oxidation of the thiol groups of the plasma proteins, thereby oxidizing particularly the low density lipoproteins (LDLs) which transport the xe2x80x9cbadxe2x80x9d cholesterol. High serum cholesteral levels and/or rapid oxidation of LDLs in plasma are the initial putative steps in the development of atherosclerosis. This is the hallmark lesion that results in coronary heart, cerebrovascular and peripheral vascular diseases. The aldehydes cause these alterations in proteins by their carbonyl group reacting with the thiols and NH2 moieties of the plasma proteins.
The present invention involves the inclusion of an antioxidant defense system within a filter to be used with tobacco products or within tobacco or within a wrapper for such tobacco products or as applied to smokeless tobacco. The present application utilizes synergistic antioxidants delivered, for example, in tobacco filters such as those for cigarettes or external filters to prevent and ameliorate free radical damage induced by smoking to the oro-pharynx, respiratory tract and lungs. The composition is supplied by inhalation through various state of the art filters. The invention in its broadest terms comprises glutathione plus the antioxidant enzymes catalase and superoxide dismutase. The composition also may incorporate glutathione in its reduced form and a co-ingredient for regenerating the reduced form of the glutathione, the co-ingredient comprising selenium as a selenoamino acid such as selenomethionine or selenocysteine. As further optional ingredients, it is contemplated that the composition may include ascorbic acid and/or one of its derivatives, a sulfur containing amino acid such as L-cysteine, L-taurine and/or L-methionine.